PSCA-CAR T Cells in Treating Patients With PSCA+ Metastatic Castration Resistant Prostate Cancer

Phase 1

Active, not recruiting

• Conditions: Metastatic Prostate Carcinoma; Castration-Resistant Prostate Carcinoma; Stage IV Prostate Cancer AJCC v8; Stage IVA Prostate Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8
• Interventions: Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate

• Registration Number: NCT03873805
• Lead Sponsor: City of Hope Medical Center

Brief Summary

This phase I trial studies side effects and best dose of PSCA-chimeric antigen receptor (CAR) T cells in treating patients with prostate stem cell antigen positive (PSCA+) castration resistant prostate cancer that has spread to other places in the body (metastatic). PSCA-CAR T cells are immune cells that have been engineered in the laboratory to kill tumor cells. This is done by using a virus to insert a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize prostate tumor cells. It is not yet known how well PSCA-CAR T cells works in killing tumor cells in patients with metastatic castration resistant prostate cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. Define the safety and tolerability of autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes (PSCA-CAR T cells) in patients with PSCA+ metastatic castration resistant prostate cancer (mCRPC).

II. Define the recommended phase 2 dose (RP2D) of PSCA-CAR T cells in patients with PSCA+ mCRPC.

SECONDARY OBJECTIVES:

I. Assess the expansion and persistence of PSCA-CAR T cells.

II. Assess clinical response based on Prostate Cancer Working Group 3 (PCWG3) criteria.

III. Assess survival outcomes (including biochemical progression free survival \[PFS\], radiographic PFS and overall survival \[OS\]).

IV. Assess serum cytokine profiles in peripheral blood pre- and post-therapy. V. Describe the PSCA expression level on tumor cells prior to CAR T cell infusion, and the relationship it may have with disease response and observed toxicities.

EXPLORATORY OBJECTIVES:

I. Characterize the phenotypes and frequencies of immune cell subsets in the peripheral blood pre- and post-therapy.

II. Enumerate and characterize tumor-infiltrating lymphocytes (TILs) pre- and post-therapy.

III. Enumerate and analyze gene expression of circulating tumor cells (CTC) pre- and post-therapy.

IV. Analyze circulating cell-free DNA (cfDNA). V. Determine the immunogenicity of PSCA-CAR T cells.

OUTLINE: This is a dose-escalation study.

Patients may receive lymphodepleting regimen at the discretion of the treating physician including fludarabine intravenously (IV) on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.

After completion of study treatment, patients are followed up at day 1, every 2 days for up to 14 days, weekly for up to 1 month, every month for up to 1 year, and then annually for up to 15 years.

Study Timeline

• Study First Submitted: 2019-03-11
• Study First Submitted QC: 2019-03-12
• Study First Posted: 2019-03-13
• Study Start: 2019-08-20
• Primary Completion: 2022-08-20
• Results First Submitted: 2023-09-11
• Results First Submitted QC: 2023-10-16
• Results First Posted: 2023-10-18
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-24
• Last Update Posted: 2024-04-29
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 14

Inclusion Criteria

• All participants must have the ability to understand and the willingness to sign a written informed consent

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 or KPS ≥70%.

• Documented castration resistant prostate cancer (mCRPC) (Note: castration will be defined by a testosterone < 50 ng/dL achieved by orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist/antagonist therapy)

  • Documented PSCA+ tumor expression as evaluated by City of Hope (COH) Pathology Care

  • Progression of disease manifest by one of the following means during treatment with at least one advanced androgen targeted therapy (e.g., abiraterone or enzalutamide)

    • Rising PSA documented on 2 occasions at least 7 days apart, with absolute increase > 2 ng/dL despite testosterone < 50 OR
    • Radiographic evidence of new metastatic foci on computed tomography (CT) or bone scan, or soft tissue progression by Response Evaluation Criteria in Solid Tumors (RECIST)

• Prior chemotherapy with cabazitaxel and/or docetaxel is allowed but not required. If there has been prior chemotherapy, at least 2 weeks must have elapsed prior to leukapheresis

• Prior radiotherapy is allowed provided it was not administered to the only evaluable site of disease and was > 14 days prior to leukapheresis

• No known contraindications to leukapheresis, steroids or tocilizumab

• Total serum bilirubin =< 2.0 mg/dL (to be performed within 42 days of signing the main study consent)

  • Patients with Gilbert syndrome may be included if their total bilirubin is =< 3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN

• Aspartate aminotransferase (AST) < 5 x ULN (to be performed within 42 days of signing the main study consent)

• Alanine aminotransferase (ALT) < 5 x ULN (to be performed within 42 days of signing the main study consent)

• Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (to be performed within 42 days of signing the main study consent)

• Cardiac function (12 lead-electrocardiography [ECG]) without acute abnormalities requiring investigation or intervention (to be performed within 42 days of signing the main study consent)

• Left ventricular ejection fraction > 40% (to be performed within 42 days of signing the main study consent)

• Participants of reproductive potential must agree to use acceptable birth control methods throughout study therapy and for 3 months after final dose of study treatment

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Exclusion Criteria

• Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the main consent
• Participants with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder
• History of allergic reactions attributed to compounds of similar chemical or biologic composition or other agents used in this study
• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
• History of stroke or intracranial hemorrhage within 6 months prior to signing the main consent
• History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for >= 3 years
• Uncontrolled active infection
• Active hepatitis B or hepatitis C infection
• Human immunodeficiency virus (HIV) infection
• Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (PSCA CAR T cells)	Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes	Patients may receive lymphodepleting regimen (either standard or modified) including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. The study PI and the protocol team will choose a chemotherapy regimen, for lymphodepletion prior to the PSCA-CAR T cell infusion (with the exception of cohorts 1 and -1 which will not receive lymphodepletion), based on the research participant's disease type and prior therapies. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.
Treatment (PSCA CAR T cells)	Fludarabine	Patients may receive lymphodepleting regimen (either standard or modified) including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. The study PI and the protocol team will choose a chemotherapy regimen, for lymphodepletion prior to the PSCA-CAR T cell infusion (with the exception of cohorts 1 and -1 which will not receive lymphodepletion), based on the research participant's disease type and prior therapies. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.
Treatment (PSCA CAR T cells)	Cyclophosphamide	Patients may receive lymphodepleting regimen (either standard or modified) including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. The study PI and the protocol team will choose a chemotherapy regimen, for lymphodepletion prior to the PSCA-CAR T cell infusion (with the exception of cohorts 1 and -1 which will not receive lymphodepletion), based on the research participant's disease type and prior therapies. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.
Treatment (PSCA CAR T cells)	Fludarabine Phosphate	Patients may receive lymphodepleting regimen (either standard or modified) including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. The study PI and the protocol team will choose a chemotherapy regimen, for lymphodepletion prior to the PSCA-CAR T cell infusion (with the exception of cohorts 1 and -1 which will not receive lymphodepletion), based on the research participant's disease type and prior therapies. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing a Dose-limiting Toxicity (DLT)	Up to 28 days post treatment	Defined by any grade 3 or NCI CTCAE toxicities and modified CRS grading as applicable.
Grade 3 Toxicity Profile	Up to 32 months	Grade 3 toxicity profile as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 and modified Cytokine Release Syndrome (CRS) grading as applicable post chimeric antigen receptor (CAR) T cell infusion.

Secondary Outcome Measures

Name	Time	Method
Expansion of CAR T Cells	Up to 28 days post treatment	Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid \[DNA\]) will be described.
Percent of Participants Achieving Stable Disease	Up to 1 year post treatment	Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for response based on Prostate Cancer Working Group 3 (PCWG3) criteria.
Percent of Participants Alive at Six Months	From CAR T cell infusion to death from any cause or last contact date, assessed up to 6 months	Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated.
Percent of Participants With CAR T Cells Persistence at Day 28	Days 28 post infusion	Persistence is defined as CAR T cells comprising at least 7.5 copies/ug of DNA of total CD3 cells.

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States